(+)-(2R,5S)-4-[4-cyano-3-(trifluoromethyl)phenyl]-2,5-dimethyl-N-[6-(trifluoromethyl)pyridin-3- yl]piperazine-1-carboxamide (YM580) as an orally potent and peripherally selective nonsteroidal androgen receptor antagonist

  • J Med Chem. 2006 Jan 26;49(2):716-26. doi: 10.1021/jm050293c.
Isao Kinoyama  1 ,  Nobuaki Taniguchi ,  Akira Toyoshima ,  Eisuke Nozawa ,  Takashi Kamikubo ,  Masakazu Imamura ,  Akira Matsuhisa ,  Kiyohiro Samizu ,  Eiji Kawanimani ,  Tatsuya Niimi ,  Noritaka Hamada ,  Hiroshi Koutoku ,  Takashi Furutani ,  Masafumi Kudoh ,  Minoru Okada ,  Mitsuaki Ohta ,  Shin-ichi Tsukamoto
Affiliations
  • 1. Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki 305-8585, Japan. [email protected]
PMID: 16420057 DOI: 10.1021/jm050293c
Abstract

A novel series of trans-N-aryl-2,5-dimethylpiperazine-1-carboxamide derivatives was synthesized and their Androgen Receptor (AR) antagonist activities and in vivo antiandrogenic effects were evaluated. Pharmacological assays indicated that compound 33 was a potent AR antagonist, and subsequent optical resolution provided (+)-(2R,5S)-4-[4-cyano-3-(trifluoromethyl)phenyl]-2,5-dimethyl-N-[6-(trifluoromethyl)pyridin-3-yl]piperazine-1-carboxamide (33a, YM580) which exhibited the most potent antiandrogenic activity. Unlike bicalutamide, compound 33a decreased the weight of rat ventral prostate in a dose-dependent manner (ED(50) = 2.2 mg/kg/day), and induced the maximum antiandrogenic effect, comparable to that of surgical castration, without significantly affecting serum testosterone levels. Compound 33a is a promising clinical candidate for Prostate Cancer monotherapy.

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